Is sarcopenia a real concern in ankylosing spondylitis? A systematic literature review

Key summary points Aim Explore the association between sarcopenia and spondyloarthritis (SpA), particularly ankylosing spondylitis (AS), with a focus on muscle mass, strength, and axial SpA. Findings The occurrence of pre-sarcopenia or probable sarcopenia was more prevalent than sarcopenia, particularly marked by a significant reduction in muscle strength. The association of pre-sarcopenia with elevated AS disease activity suggests a potential influence of chronic inflammation on muscle health. Message Evidence points to a correlation between AS and premature muscle strength loss, suggesting a potential onset of sarcopenia, underscoring the importance of early intervention strategies for successful aging in individuals with AS. Supplementary Information The online version contains supplementary material available at 10.1007/s41999-024-00968-1.


Introduction
Ankylosing spondylitis (AS) is an inflammatory disease categorized under seronegative spondyloarthritis (SpA).This condition typically manifests in individuals aged 20-45, primarily affecting axial regions, but can also involve peripheral joints and enthesis with symptoms like synovitis, enthesitis, and dactylitis [1].Common early symptoms include inflammatory back pain and characteristic stiffness exacerbated by inactivity [1].Extra-articular manifestations such as uveitis, psoriasis, mucositis, and chronic inflammatory bowel disease may also occur [1].Chronic pain and joint dysfunction in AS lead to a more sedentary lifestyle, which worsens with acute inflammation [1,2].Recent research indicates a molecular connection between muscle, joints, entheseal tissues, and bone health with the Interleukin 23 (IL23) and Transforming Growth Factor beta (TGFbeta) pathways potentially playing a major role in musculoskeletal tissue changes [3].
By the same mechanisms, poor physical activity and chronic inflammation induce chronic complications, such as osteoporosis [4].In the last decades, there has been much debate as to whether sarcopenia could also be a complication associated with AS [5].Sarcopenia is defined according to the European working group on sarcopenia in older people (EWGSOP) criteria as an abnormally low muscle mass associated with low skeletal muscle strength and/or poor physical performance, leading to an increased risk of unfavorable outcomes such as physical disability and poor quality of life [6].Primary sarcopenia usually is associated with older age, as it is linked to physiological muscle aging [7].Considering the pathophysiology of SpA, we would expect an increased incidence of secondary sarcopenia in patients with AS, especially in the presence of active disease activity.Despite these considerations, current evidence fails to establish the exact prevalence of sarcopenia in AS, possibly due to heterogeneous studies and varying definitions of sarcopenia.
Therefore, this systematic literature review aims to identify accessible studies examining poor muscle health associated with AS.The goal is to critically appraise these studies in light of the latest hypothesis on AS pathophysiology and reevaluate the potential role of low muscle mass and/or strength in exacerbating AS.Recognizing decreased muscle health in AS patients should prompt preemptive and therapeutic, system-specific interventions to improve function and quality of life.

Eligibility criteria
Inclusion criteria were: (a) studies investigating the relationship between muscle mass and muscle strength, and axial SpA; (b) studies that compared patients affected by axial SpA to healthy controls or different rheumatic disease; (c) population aged ≥ 18 years; (d) defined and validated criteria to assess the presence of sarcopenia; and (e) published studies on the topic of interest using any study methodology, with a focus primarily on case-control, prospective, and cross-sectional studies; (f) availability of full text of the original research paper.
Exclusion criteria were: (a) case reports, abstracts, letters, and editorials; (b) studies not written in English; (c) animal model studies; (d) articles focusing on the therapeutic effect on muscle health of any type of drug (such as biotechnological drugs).

Information sources
The Scopus, PubMed, and Web of Science databases were searched from any date to November 2023.

Search strategy
The databases were searched for the terms "ankylosing spondylitis", "axial spondyloarthritis", "sarcopenia", "cachexia" and "muscle strength".The detailed search string utilized for bibliographic retrieval is provided in the supplementary materials.

Selection and data collection process
This review adheres to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA-http:// www.prisma-state ment.org/) and Meta-analysis of Observational Studies in Epidemiology guidelines [8].References cited in the selected papers were examined to identify any other potential articles.After selection of papers by a first reviewer (C.C.), the whole process was repeated and confirmed by a second reviewer (M.V.P.) to ensure validity of inclusion.Differences of opinion were discussed until consensus on inclusion or exclusion was reached with a third reviewer (L.S.).The Rayyan software, a web-based tool tailored for systematic review coordination, was utilized to expedite the screening phase.The methodological quality of each article selected for inclusion in the review was assessed by two reviewers (C.C., M.V.P) using the Newcastle-Ottawa Scales (NOS) for observational studies and for case-control studies.

Data extraction
Titles and abstracts of selected articles were screened for relevance.The following data were extracted: (1)

Results
A total of 190 studies were identified from the database searches, of which 51 duplicates were excluded.After reviewing the titles and abstracts, 101 records were discarded leaving 38 papers whose full manuscripts were examined in detail.A further 28 papers were discarded as ineligible, leaving 10 studies for full appraisal.Four additional records were added through a previous systematic review (Fig. 1).NOS scores of the included articles are shown in Tables 1 and 2. After evaluation by two researchers, the studies received an average NOS score of 6.0, indicative of good quality.
The individual outcomes are briefly discussed below.Supplementary Table 1 lists all the selected studies highlighting the main results about any positive or negative association between axial SpA and muscle health.

Muscle mass
Only three authors reported low appendicular mass values in AS patients [10,19,20].The case-control study by El Maghraoui et al.-2016 was conducted on 134 male individuals (67 with AS, mean age 40.7 ± 11.0 years) aiming to define the prevalence of pre-sarcopenia and sarcopenia, and to analyze its relationship with rheumatic disease parameters [10]; a significant reduction of appendicular lean mass (22.2 ± 3.0 vs. 23.4 ± 3.3, p = 0.033) but not appendicular mass index was reported in AS patients [10].Two other case-control studies conducted on 10 (mean age 39 ± 4.2 years) [19] and 19 (mean age 53 ± 12) [20] male patients, respectively, reported lower appendicular lean mass values (measured by Dual-Energy X-ray Absorptiometry-DXA) when compared to healthy controls [(8.3 ± 0.9 vs. 8.8 ± 0.8 kg/m 2 , p = 0.02) and (21.9 ± 2.8 vs. 24.9± 4.2 kg), respectively] [19,20].The measure of total lean mass by DXA did not show any significant differences between cases and controls in the studies by Toussirot et al. [13] and Dos Santos et al. [12]; the former considered 71 patients with AS (median age 38 years) compared to as many controls [13], the latter comprised 39 male patients (37.6 ± 9.1 years) with rheumatoid disease [12].Finally, two recent studies aiming to ascertain the prevalence of sarcopenia in AS patients described low skeletal muscle mass in these patients, with no significant differences as it relates to lean mass (total or appendicular) when compared to controls [14,15].

Muscle strength
The studies related to the measurement of muscle strength considered heterogeneous tools: to assess the strength of the hand (handgrip dynamometer) and the strength of the lower extremity (knee-extension device, isokinetic dynamometer).Among the studies that analyzed differences on lean mass, two also focused on muscle strength, though no significative differences were reported when handgrip dynamometer was applied [19,20].In the study of Marcora et al. [20], handgrip strength was 40.1 ± 8.0 kg in AS patients vs. 40.4± 8.9 kg in healthy controls; however, knee extensors strength was significantly lower in the rheumatic patients in both case-control studies (181 ± 67 Nm vs 228 ± 72 Nm p = 0.04 and 187 ± 38 Nm vs 226 ± 29 Nm, p = 0.03, respectively) [19,20].Similar results were obtained in the recent study by Kao et al. [11], which focused on 51 AS patients and controls (mean age 41.7 ± 11.8 years), with low handgrip dynamometer scores in affected patients vs. healthy controls (30.23 ± 11.0 vs. 38.76± 8.23, p = 0.003).The Authors underlined that there were no correlations between muscle strength and disease activity, regardless of the instrument used to evaluate it [11].
The prospective study of Demirkapi et al. [9], enlisted 60 patients (39 with AS; mean age 39.3 ± 8.6 years), with the aim to evaluate muscle performance in these patients using an isokinetic dynamometer.Peak torque values in AS patients were lower than in controls both in flexors and extensors muscles at 60°/second and 180°/second angular velocity [9].
The two case-controls studies of Sahin et al. [16,17] used an isokinetic dynamometer to compare strength of ankle plantarflexor/dorsiflexor muscles [16] and knee extensor/flexor muscle groups [17] in 27 AS patients (mean age 37.04 ± 8.85 years) and healthy controls.Among patients, the dynamometer measurements were lower in all angular velocities (p < 0.05 for all).

Sarcopenia
Of the five studies that focused on sarcopenia [10,14,15,21,22], three considered the most recent guidelines for the diagnosis of this musculoskeletal disease [14,15,22].The French study by Merle et al. 2023, reported a significant percentage of patients with probable sarcopenia (21% vs 7% in controls, p < 0.01), i.e. reduction of grip strength [14].Although the authors did not find a direct relationship between sarcopenia and rheumatic disease activity, they proposed a questionnaire (SarQoL) to assess patients' perception of physical, psychological and social quality of life, finding that patients with lower grip strength scores also had lower SarQoL scores (44.3 ± 11.6 vs. 61.0± 15.8, p < 0.001) [14].Similarly, no sarcopenic patients were detected in the case-control study by Neto et al. [15]: a reduction in skeletal muscle mass and strength (8.3% vs. 4.2% and 8.3% vs. 0% of the sample, respectively) was reported in young AS patients, albeit without ever reaching statistical significance [15].
A recent study from Thailand considered the Asian Working Group for Sarcopenia 2019 guidelines for the diagnosis of sarcopenia [22].The authors endeavored to evaluate sarcopenia in a cohort of 104 patients (mean age 42 years) diagnosed with AS.Among these, 26 individuals received biologics and anti-TNF agents were the most frequently prescribed [22].Sarcopenia was identified in 89 subjects (85.6%), with impaired physical performance presence in 23 (22.1%).Sarcopenic patients exhibited older age and lower BMI compared to their non-sarcopenic counterparts, with no discernible differences in sex, disease duration, activity or severity, and use of biologics and glucocorticoids [22].Nevertheless, sarcopenic patients exhibited a higher incidence of osteoporosis compared to their non-sarcopenic counterparts, with 7 subjects (6.7%) diagnosed with osteosarcopenia [22].In multivariate analyses, older age, lower BMI, and higher BASFI were identified as independent factors associated with sarcopenia in patients with AS (22).

Discussion
Sarcopenia is typically described as a condition of the aging process.There is growing interest in the secondary forms of sarcopenia, linked to immobilization/bed rest, osteoporosis and chronic inflammation, typical of rheumatic diseases [26,27].This comprehensive systematic review included 14 articles encompassing a population of 596 patients affected by AS.Our review aimed to assess the prevalence of pre-sarcopenia, probable sarcopenia, and sarcopenia in patients with AS.Additionally, we aimed to separately examine two pivotal aspects of muscle health, namely muscle mass and muscle strength.This approach stems from the recognition that muscle strength and muscle mass, as distinct health indicators, are regulated through different mechanisms.While the methodologies for evaluating muscle mass, strength, and sarcopenia varied among studies, the collective evidence suggests a potential correlation between compromised muscle health and AS in adults, irrespective of age.
AS can manifest as systemic fatigue and generalized stiffness; however, the primary impairment is notably observed in the pelvic, lumbar, dorsal, and cervical muscles, contingent on the extent of disease involvement.Despite the limited examination of trunk muscles' function in a singular study [14], a noteworthy decline in muscle strength was identified, suggesting that muscle strength might serve as a significant symptom in SpA [14].This observation warrants further investigation for more comprehensive characterization.
While the specific mechanisms contributing to muscle damage are still debated, our hypothesis suggests that inflammation, reduced physical activity, a sedentary lifestyle, glucocorticoid therapy, and neuromuscular impairment may all play integral roles (Fig. 2).In the context of sarcopenia development, inflammation assumes a crucial role [28][29][30].Elevated inflammation and disease activity may lead to sarcopenia, compromising muscle performance, reducing quality of life, and contributing to the overall burden of the disease [28].The pathogenesis of ankylosing spondylitis involves a complex interplay of genetic and environmental factors.Aberrantly stimulated innate and innatelike cells, such as γδ T cells, group 3 innate lymphoid cells, and mucosa-associated invariant T cells, activate the IL-23/-17 axis, resulting in a local pro-inflammatory environment [31,32].In turn, inflammatory cytokines activate various molecular pathways associated with skeletal muscle wasting, creating an imbalance between protein synthesis and catabolism.Moreover, a recent literature review has highlighted how muscle depletion and sarcopenia are closely linked to neuromuscular degradation, a process quantifiable through the assessment of biomarkers indicating neuromuscular junction (NMJ) stability, such as the C-terminal agrin fragment (CAF) [33].The presence of CAF in the bloodstream correlates with NMJ decline and muscle denervation, showing a significant association with muscle mass loss [33].Consequently, CAF serves as an early indicator of sarcopenia, both in its primary and secondary forms [33].
It's noteworthy that the participants in these studies were generally young, with four studies involving biological drug treatments [8][9][10]13], and in another four studies, BASDAI values were notably low [14][15][16]18].This factor may partially account for the lower level of significance observed in some results.Nevertheless, the majority of studies consistently revealed lower muscle mass and/or muscle strength in the AS population compared to controls, indicating residual muscle dysfunction even in a state of low disease activity.Another significant contributor to muscle damage is physical inactivity [34].The onset of the disease and its exacerbations are associated with reduced activity, fatigue, and progressive impairments, leading to disability and the need for assistance in even the simplest daily tasks [35].Additionally, neuromuscular impairment-manifested as local inflammation and damage to tendons and ligaments-may contribute to pre-sarcopenic changes in patients with AS, resulting in a loss of coordination of voluntary muscle movement [36].
Hence, non-pharmacological interventions such as physical exercise are crucial for maintaining and improving neuromuscular function, mobility, and functional capacity, ultimately reducing pain and preventing joint deformity [37,38].Previous studies have highlighted an association between disease activity, a sedentary lifestyle, and poor quality of life, serving as independent risk factors for comorbidities like sarcopenia in patients with AS.Conversely, physical activity is linked to better function, exercise capacity, and spinal mobility [38][39][40].This underscores the importance of a multidisciplinary approach in managing AS patients, involving close collaboration between healthcare professionals such as physiatrists and physiotherapists.These professionals play a crucial role in facilitating the functional recovery of patients, thereby improving their quality of life and mitigating complications [41].
Initiating physical therapy, which includes kinesiotherapy and rehabilitation programs involving exercises and mind-body techniques, early in the course of AS is imperative and should be an integral aspect of disease management [41][42][43].Physical exercises can be undertaken independently or under supervision [41].The latter entails the instruction and demonstration of exercises, coupled with open discussions about feelings and concerns with the physiotherapist, fostering a trusting relationship that may enhance patients' adherence to physiotherapy programs [44].A recent metaanalysis has demonstrated that supervised physiotherapy is comparable to home-based exercises but more effective than usual care in ameliorating disease activity, enhancing functional capacity, and alleviating pain in patients with AS [44].Notably, exercises such as Pilates, aquatic exercises, aerobic and stretching exercises, ultrasound therapies, cardiovascular training, and Baduanjin Qigong exercise were considered in this context [44].Furthermore, cryotherapy and kinesiotherapy yielded promising results in AS patients, with the BASDAI index decreasing by approximately 40% compared to baseline in 32 patients undergoing whole-body cryotherapy followed by kinesiotherapy, as opposed to 16 patients treated with kinesiotherapy alone [45].However, as of now, there is no specific non-pharmacological protocol, and clear indications regarding which exercises are most beneficial to patients remain elusive [41,44].A crucial aspect in comprehending the pathogenesis of sarcopenia in patients with AS is the use of drugs for pain management.Pain, considered the most important patientreported outcome (PRO) in rheumatology, significantly impacts health-related quality of life [46].Commonly used medications for pain management and inflammation in AS include non-steroidal anti-inflammatory drugs (NSAIDs), glucocorticoids, opioids, and neuromodulators [46].Glucocorticoids have an immediate detrimental effect on muscle health, altering sarcolemmal excitability, protein synthesis, and myogenesis, ultimately reducing muscle strength [7,47].While a recent systematic literature review reported that biologic disease-modifying antirheumatic drugs (bDMARDs) play a role in improving muscle mass and strength in SpA patients, their impact on total lean mass remains insignificant [7].However, our results do not provide clarity on whether the damage induced by disease activity and glucocorticoids can be fully reversed by bDMARDs alone.Our impression aligns with the suggestion in the 2022 ASAS-EULAR guidelines that bDMARDs therapy alone may not be sufficient for the complete restoration of healthy muscle [41].

Limitations
We would be remiss not to mention some of the limitations of our review.Firstly, the lack of longitudinal studies that uniformly assessed strength deficit and loss of muscle mass; cross-sectional studies are not sufficient to evaluate the real impact of sarcopenia as a suspected consequence of AS.Secondly, although most AS patients are commonly treated with bDMARDs nowadays, we did not evaluate the effects of these drugs on muscle health as it was beyond the scope of our study.Furthermore, we did not consider severe sarcopenia, instead focusing solely on muscle mass and strength parameters.Another limitation is that only two studies considered the latest guidelines to ascertain the presence of sarcopenia, thus making the results regarding its prevalence in patients with AS very heterogeneous.Moreover, these definitions are usually applied to older people, while AS predominantly affects young adults.The studies we retrieved were mostly carried out in higher-income countries, which are not representative of the world's general population.Only one study was conducted in low-and middle-income countries (LMIC) [22], which may limit the applicability of our findings.

Conclusions
In conclusion, our systematic review found evidence that muscle damage, especially reduced power and strength, are associated with AS.These patients may benefit from early and targeted interventions to improve muscle health and therefore quality of life.We hope that our work can contribute to reflecting on an emerging issue for these young patients, which has the potential to be prevented and treated in order to ensure successful aging for them.Larger prospective studies are warranted to better understand the pathophysiological mechanisms and the impact of other risk factors for sarcopenia.

Fig. 1
Fig. 1 PRISMA flow diagram of the process of (and reasons for) including and excluding studies

Fig. 2
Fig. 2 Potential mechanisms in the association between Ankylosing Spondylitis and muscle health.Inflammation and damage, together with psychosocial factors, are the main determinants of the impact of ankylosing spondylitis on physical function.A decreased physical activity pairs with the increase of disability and assistential needs.Physical inactivity and progressive neuromuscular dysfunc-

Table 1
Study quality assessment using Newcastle-Ottawa scale for observational studies

Table 2
Study quality assessment using Newcastle-Ottawa scale for case-control studies *Each asterisk represents if individual criterion within the subsection was fulfilled NOS Newcastle-Ottawa quality assessment scale